Abstract 666: Efficacy and Safety of Zoledronic Acid 5 mg in Preventing Fractures in Men and Women With Prevalent Hip Fracture: The HORIZON-Recurrent Fracture Trial
Assil Saleh, M.D.
Authors:
K. Lyles, C. Colon-Emeric, J. Magaziner, J. Adachi, C. Pieper, L. Hyldstrup, C. Mautalen, C. Recknor, K. Moore, C. Lavecchia, J. Zhang, P. Mesenbrink, E. Eriksen, S. Boonen.
Background:
Hip fractures are common and are a major source of increased morbidity and mortality in the elderly. Once a hip fracture occurs, the incidence of a subsequent osteoporotic fracture is significantly higher than in age-matched controls (10.4 per 100 patients per year). Despite this, the majority of patients with such fractures do not receive treatment for secondary prevention. Zoledronic acid has been recognized as one of the most efficacious bisphosphonates to treat postmenopausal osteoporosis, and it has been associated with reduction in vertebral, hip and non-vertebral fractures. In addition, it may promote improved compliance due to its convenient annual dosing regimen. The objective of this study was to assess whether annual zoledronic acid therapy in patients with prevalent hip fractures protects against the development of new fractures.
Methods:
This was an international randomized, multi-center, double-blind, placebo-controlled trial. A total of 2127 participants with recent hip fractures were enrolled. 1065 were randomized to yearly intravenous zoledronic acid (5 mg), and 1062 received placebo. The study drugs were administered within 90 days of the surgical repair of a hip fracture and then annually for the duration of the study. Supplemental vitamin D and calcium was administered to all subjects, and vitamin D deficiency was vigorously treated prior to study drug administration.
Patients were followed for up to 5 years; median follow up was 1.9 years. The primary end point was a new clinical fracture, and secondary end points included change in bone mineral density in the non-fractured hip (measured annually with dual-energy x-ray absorptiometry), new vertebral, nonvertebral, and hip fractures, and safety-related endpoints, including death.
Results:
Results were published in N Engl J Med. 2007; 357(18):1861-2.
Both treatment groups were composed of mostly white females (~75%) and had comparable demographics. Osteoporosis was diagnosed in fewer than half of subjects by bone DXA scan at the time of fracture. The incidence of new fractures was 35% lower in participants who received zoledronic acid compared to placebo. There was significant reduction in relative risk of new clinical fractures in non-vertebral and vertebral fractures, and a non-significant reduction in hip fractures.
Bone mineral density increased at the total hip and femoral neck in the zoledronic acid group and declined in the placebo group at 12, 24 and 36 months. The difference between the groups was statistically significant.
There was a 28% reduction in the relative rate of all-cause mortality in the zoledronic acid group compared to placebo. Cardiovascular mortality accounted for 1% and 1.7% of all deaths respectively in the zoledronic acid and placebo groups.
The overall rate of adverse events was virtually identical in both groups but significantly more mylagias, bone and musculoskeletal pain, and pyrexia were reported in the zoledronic acid group. There was no evidence of delayed fracture union with treatment with zoledronic acid within 90 days of surgical hip fracture repair.
Conclusions:
In patients with prevalent hip fractures, treatment with intravenous yearly zolendronic acid was well tolerated and associated with a significant reduction in the incidence of vertebral and non-vertebral fractures. Moreover, there was a 28% relative reduction in all-cause mortality in the zoledronic acid treatment arm, which in part may be due to the reduction in the incidence of new fractures.
Editorial Comment:
This is a novel and well conducted study addressing secondary prevention of osteoporotic fractures in patients with prevalent osteoporotic hip fractures. It is unfortunately frequent that patients with osteoporotic fractures, particularly of the hip, do not always receive osteoporosis therapy. They are thus at increased risk of developing future fractures, resulting in increased morbidity and mortality. Zolendronic acid may be an effective, safe, and easily administered therapy to reduce this significant public health problem.
The ethical issue of withholding critical therapy in an at-risk population with significant osteoporosis and concomitant serious morbidity and mortality is highlighted by this study. The authors took pains to remind the reader that only patients unable or unwilling to take an oral bisphosphonate were enrolled.
